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Long-Term Animal Model of Venovenous Extracorporeal Membrane Oxygenation with Atrial Septal Defect as a Bridge to Lung Transplantation

Camboni, Daniele*; Rojas, Alvaro; Sassalos, Peter; Spurlock, David; Koch, Kelly L.; Menchak, Sarah; Singleton, Jennifer; Boothman, Erika; Haft, Jonathan W.; Bartlett, Robert H.; Cook, Keith E.†‡

doi: 10.1097/MAT.0b013e3182a91ddb
Adult Circulatory Support

This study evaluated the effectiveness of an atrial septal defect (ASD) with venovenous extracorporeal membrane oxygenation (vv-ECMO) as a bridge to transplantation. Sheep (56 ± 3 kg; n = 7) underwent a right-sided thoracotomy to create the ASD (diameter = 1 cm) and place instrumentation and a pulmonary artery (PA) occluder. After recovery, animals were placed on ECMO, and the PA was constricted to generate a twofold rise in right ventricular (RV) systolic pressure. Sheep were then maintained for 60 hours on ECMO, and data were collected hourly. Five sheep survived 60 hours. One sheep died because of a circuit clot extending into the RV, and another died presumably because of an arrhythmia. Mean right ventricular pressure (mRVP) was 19 ± 3 mm Hg at baseline, averaged 27 ± 7 mm Hg over the experiment, but was not statistically significant (p = 0.27) due to one sheep without an increase. Cardiac output was 6.8 ± 1.2 L/min at baseline, averaged 6.0 ± 1.0 L/min during the experiment, and was statistically unchanged (p = 0.34). Average arterial oxygen saturation and PCO2 over the experiment were 96.8 ± 1.4% and 31.8 ± 3.4 mm Hg, respectively. In conclusion, an ASD combined with vv-ECMO maintains normal systemic hemodynamics and arterial blood gases during a long-term increase in RV afterload.

*Department of Cardiothoracic Surgery, University Hospital Regensburg, Regensburg, Germany; Department of Surgery, University of Michigan, Ann Arbor, Michigan; and Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.

Submitted for consideration April 2013; accepted for publication in revised form July 2013.

Disclosures: The authors have no conflicts of interest to report.

This study was partially supported by grant RO1HL069420-0 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. Daniele Camboni was partially supported by the German Research Foundation (DFG CA 861/1-1).

Reprint Requests: Daniele Camboni, Department of Cardiothoracic Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. Email: daniele.camboni@ukr.de.

Lung disease is the cause of one in seven deaths in the United States, totaling 400,0000 Americans each year.1 The burden caused by pulmonary pathologies can also be inferred by the fact that between 10% and 30% of heart failure admissions in the United States are the result of cor pulmonale, and the National Institutes of Health (NIH) pulmonary hypertension registry reports that 50% of death results from right ventricular (RV) failure.2 Currently, the only treatment option for chronic irreversible pulmonary failure is lung transplantation. After transplantation, RV strain normally decreases, and remodeling processes reestablish normal RV physiology spontaneously.3 Unfortunately, the demand for donor lungs has steadily outgrown the supply. This mismatch between the demand and the available donor organs leads to the fact that approximately one fourth of patients on the lung transplant waiting list die per year in the United States.4

Unlike renal or cardiac replacement therapy, the current methods for supporting patients with end-stage lung disease are not sufficiently refined to act as a long-term bridge to transplantation. An atrial septostomy is occasionally applied to unload the RV and bridge patients experiencing RV failure to lung transplantation.5,6 Right-to-left atrial shunting increases cardiac output (CO), resulting in increased oxygen delivery despite mild arterial desaturation. Because of the desaturation, patients with severely impaired gas exchange are not considered suitable candidates for atrial septostomies, limiting the application to a small group of patients.

Hypothetically, patients experiencing gas exchange deficiency could be supported by venovenous extracorporeal membrane oxygenation (vv-ECMO) to condition the venous blood before the septostomy. Recent major advances in ECMO technology have enabled patients to be supported with relative safety for several weeks up to months facilitating even extubation.7,8 The possibility of extubation is of particular importance because a spontaneously breathing and alert transplant candidate is considered the ideal recipient because of a less severe level of physical deconditioning, in particular of respiratory muscles.

Previous studies conducted at our institution have shown the effectiveness of an atrial septostomy combined with vv-ECMO in an acute large animal model.9,10 This large animal study was designed to evaluate the long-term effectiveness of this new approach as a bridge to lung transplantation for respiratory and RV failure.

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Materials and Methods

All animals received care compliant with the “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” prepared by the National Academy of Sciences and published by the NIH. The study was approved by the University of Michigan Committee on Use and Care of Animals.

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Surgical Preparation

Adult male sheep (56 ± 3 kg, n = 7) were anesthetized using a standard protocol as previously described and used by our laboratory.11 Antibiotic prophylaxis was performed no more than the day of surgery with two intravenous doses of 1 g of Nafcillin (Sandoz, Inc., Princeton, NJ) and 120 mg of Gentamicin (APP Pharmaceutical, LLC, Schaumburg, IL). The ventilator (Narkomed 600, North American Dräger, Telford, PA) was set initially at a tidal volume of 10 ml/kg and a frequency of 12–15 breaths/min. It was adjusted as needed to maintain the arterial PCO2 between 35 and 45 mm Hg with a peak inspiratory pressure <30 cm H2O. Venous access was achieved with a 9 Fr percutaneous sheath introducer (Arrow International, Inc., Reading, PA). A pulmonary artery (PA) catheter (Edwards Lifesciences, LLC, Irvine, CA) was positioned in the outflow tract of the RV to measure continuous RV pressure. Arterial access was established by carotid catheterization using polyvinyl chloride tubing (Abbott Critical Care Systems, North Chicago, IL). The arterial catheter was connected to a fluid-coupled pressure transducer (Abbott Critical Care Systems) to monitor arterial pressure that was displayed continuously (Marquette Electronics, Milwaukee, WI).

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Surgery

A right-sided thoracotomy was performed, including partial resection of the fourth rib. A perivascular flow probe (24PAX Model, Transonic Systems, Ithaca, NY) was placed around the ascending aorta and attached to a flow meter (T206, Transonic Systems) to measure continuous CO. A 20 mm diameter vascular occluder (Access Technologies, Skokie, IL) was positioned around the PA to establish RV afterload. In all sheep, the vascular occluder was inflated until there was a 50% decrease in CO and the RV systolic pressure was doubled. This degree of acute reduction in CO and increase in RV afterload is lethal according to our previous experiments. The degree of inflation was noted for use after recovery (mean volume of inflation: 2.01 ± 0.30 ml), and the occluder was then deflated.

The atrial septal defect (ASD) was performed on a beating heart through a double purse string suture on the right atrial appendage by digital perforation of the fossa ovalis and the membranous part of the atrial septum. A modified 27 Fr dual lumen cannula (Avalon Laboratories, Rancho Dominguez, CA) was introduced through the right jugular vein to establish drainage from the inferior vena cava and reinfusion directly into the right atrium. The catheter’s drainage port from the superior vena cava was blocked to limit recirculation.

Chest tubes (36 Fr) were placed and attached to a dry suction water seal chest drainage chamber (Atrium Medical Corporation, Hudson, NH) to enable fluid drainage and lung expansion by applying 20 mm H2O negative pressure to the pleural cavity. An intercostal block was performed by injecting a long-lasting local anesthetic 0.5% Bupivacaine (Hospira, Inc., Lake Forest, IL) into the fourth and adjacent intercostal spaces. The chest was closed in three layers. The sheep was then moved to a custom-built cage that allowed sitting and standing but not turning around. During recovery and the further experimental course, the postoperative analgesic protocol consisted of intramuscular injection of 60 mg Ketorolac (Hospira, Inc.) and 0.6 mg buprenorphine (Buprenex Reckitt Benckiser Pharmaceuticals Inc., Richmond, VA) every 4–6 hours. The intercostal block with Bupivacaine was repeated as needed but was not necessary more than twice. Extubation was accomplished 3–5 hours postoperatively. A heparin drip 80 U/h (Multi-Phaser NE-1000; New Era Pump System Inc., Wantagh, NY) was started 6 hours postoperatively to achieve an activated clotting time between 200 and 300 seconds. Maintenance fluid was given at a rate between 50 and 200 ml/h, as guided by the central venous pressure (CVP), the oral fluid intake of the animal, and clinical conditions. The CVP alone was not considered reliable because of the presence of the double lumen cannula in the right atrium.

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Extracorporeal Membrane Oxygenation Circuit

The ECMO circuit consisted of a centrifugal pump (Biomedicus 520D; Medtronic, Minneapolis, MN), heater unit (ECMO-Temp; Zimmer, Dover, OH), oxygenator (Capiox SX; Terumo, Ann Arbor, MI), 3/8″ S-50 HL Medical Grade Tubing (Tygon Saint-Gobain Performance Plastics, Akron, OH), and the previously described dual lumen cannula. The circuit was primed with 1 L lactated Ringer solution mixed with 50 ml of 8.4% sodium bicarbonate solution (Hospira, Inc.). Before initiating vv-ECMO, 0.5 g iv methylprednisolone (Pfizer, New York, NY) was administered to reduce the inflammatory response to the foreign surfaces of the circuit. Venovenous ECMO flow was then initiated and maintained at 1.0–3.5 L/min according to the arterial blood gases. Pure oxygen was delivered to the oxygenator at a flow rate of 2–6 L/min based on arterial blood gases. The centrifugal pump was kept between 2,000 and 3,000 rpm.

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Experimental Procedure

Venovenous ECMO was initiated after a 12–18 hour postoperative period if the animal was standing and alert. It was initiated before that point (n = 3) if postoperative arterial PO2 fell below 60 mm Hg. A full hemodynamic and blood gas data set (Table 1) was then taken to establish the sheep’s baseline condition before reapplying the PA band. The band was reinflated to the level recorded during surgery. Blood gases and hemodynamics were then recorded every hour after surgery (Table 1). Plasma-free hemoglobin (Hb) and blood chemistry were measured daily.

The condition of the vascular occluder was tested daily by deflating the balloon for a period of 5 minutes while recording RV pressures and then reinflating it with the same amount of volume guided by simultaneous RV pressure measurement. The degree of gas exchange support by vv-ECMO was tested by daily withholding the O2 supply to the oxygenator for up to 2 minutes causing severe dyspnea in each sheep. The sheep ate and drank ad libitum over the 60 h experiment. All animals breathed spontaneously in addition to support via vv-ECMO. A face mask was attached in three animals for short periods if the oxygen saturation fell below 90% under physical activity (e.g., standing up). At the end of the experiment, the sheep were euthanized using Fatal-Plus (Vortech Pharmaceuticals, Ltd, Dearborn, MI), and a gross necropsy was performed. The patency and size of the ASD were measured during necropsy.

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Data Analysis and Statistical Evaluation

Each sheep’s hemodynamic and blood gas data were averaged over 12 hour intervals. Data for these periods were then averaged for all sheep. Data are presented as an average of this data ± standard error. Arterial oxygen delivery (DO2) was calculated as:

in which CO is the cardiac output in ml/min, Hb is the hemoglobin concentration in g/dl, SO2 is the fractional arterial oxyhemoglobin saturation, and k is the oxygen solubility in blood (3 × 10–5 ml O2/ml blood/mm Hg), and PO2 is the oxygen partial pressure in blood.

To examine the statistical effect of time on all data, linear models with correlated error structures (given the repeated measures) were fitted to the observed data using IBM SPSS 19 (Chicago, IL). The sheep/experiment number was the subject; the fixed, repeated variable was the experimental time; and the dependent variables were mean arterial pressure (MAP), CO, mean right ventricular pressure (mRVP), PO2, PCO2, Hb, and DO2. Alternative covariance structures were compared using information criteria (e.g., Akaike information criterion, Bayesian information criterion). In all cases, an autoregressive covariance structure was found to have the best fit. A Bonferroni correction was applied in contrast to prevent increases in type I error rates. p ≤ 0.05 was considered statistically significant.

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Results

All seven sheep survived creation of the ASD, placement on vv-ECMO, and PA banding. One sheep experienced circuit failure and death after 20 hours of ECMO support because of massive circuit thrombus formation, despite adequate heparin delivery (see Necropsy section). There was no obvious cause for this because activated coagulation times were always over 220 seconds in this sheep. In another animal, sudden death occurred at 20 hours. Necropsy showed a dislocation of the cannula into the RV, presumably evoking a malignant arrhythmia as the cause of death. The remaining five sheep survived the entire experimental period of 60 hours. All surviving sheep developed slight facial edema most likely because of cannulation of both jugular veins. No hemorrhage or other bleeding issues occurred, and no transfusions of red blood cells or platelets were necessary.

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Hemodynamics

The hemodynamic picture overall is of an animal that had slightly elevated CO and MAP postoperatively with a return to normal values within 12 hours. Even with excellent pain management, this is common among postoperative sheep adjusting to the recovery room and recovery cages. Cardiac output was 6.8 ± 1.2 L/min at baseline (Figure 1). It remained in a normal range for the duration of the experiment, averaging 6.0 ± 1.0 L/min thereafter, and did not vary significantly with time (p = 0.34). Mean arterial pressure averaged 93 ± 8 mm Hg at baseline and remained in the normal range thereafter, averaging 81 ± 8 mm Hg. These changes approached but were not statistically significant (p = 0.09). The heart rate averaged 127 ± 9 beats/min at baseline and varied between 119 ± 7 and 149 ± 8 beats/min thereafter (p < 0.05). There was a small trend toward increased heart rate at 60 hours, but there were no significant differences at any time when compared with baseline (p = 0.11–0.99). Mean right ventricular pressure was 19 ± 3 mm Hg at baseline. Four of the five sheep demonstrated a consistent increase in mRVP, but the fifth demonstrated a decrease in mRVP after banding. For this reason, mRVP did not increase significantly overall after PA banding (p = 0.27; Figure 2), despite a trend toward increasing pressure. The mean RVP over the experimental period was 27 ± 7 mm Hg.

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Gas Exchange

The mean arterial oxygen partial pressure (PaO2) was 93 ± 4 mm Hg at baseline, fell to 78 ± 5 mm Hg 12 hours after PA banding, and was relatively constant thereafter. Although on average PaO2 declined after PA banding, this trend was not consistent, and there was no significant change in PaO2 over the experiment (p = 0.19). Despite this small drop, the average oxygen saturation was maintained >95% at all experimental times. Hemoglobin fell slightly from 9.3 ± 0.7 g/dl to 8.9 ± 1.0 g/dl after 12 hours and then fell steadily until stabilizing after day 3 (Figure 3). As a result of hemodilution, DO2 fell from 845 ± 78 at baseline to 598 ± 45 at 24 hours (Figure 3). Thereafter, it was stable. The mean arterial carbon dioxide partial pressure averaged 30.3 ± 2.2 mm Hg at baseline, 30.3 ± 1.6 mm Hg after 12 hours, and 31.8 ± 3.4 mm Hg over the entire period after PA banding (Figure 4). This change was small and clinically insignificant but did approach statistical significance (p = 0.08). Withholding the O2 supply to the oxygenator lead to severe dyspnea in all animals.

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Necropsy

The correct positioning of the ECMO cannula was affirmed in all but one animal. In this latter animal, the cannula was found in the RV, as discussed previously. In the other premature death, clots were found around and in the cannula, as well as in the right atrium, RV, and PA. The PA occluder was also affirmed functional in every animal. The ASD diameter averaged 1 ± 0.2 cm. A slight interstitial edema was found in every animal combined with slight pleural effusions. The lungs appeared normal, and no signs of embolism were found in the liver, kidneys, and intestine. The brain was not examined.

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Discussion

Because of the consistent shortage of available donor lungs, much effort has been spent developing feasible therapies and devices to support patients on the waiting list. A bridge to lung transplant should provide full gas exchange at rest and possibly with moderate exertion and alleviate RV strain. Furthermore, it must do this for a few weeks to months. The ideal bridge to lung transplantation device should also be wearable to offer mobility and potentially home use. Unfortunately, no available method or device has met these criteria to date. One current technique is pumpless arteriovenous CO2 removal using the Novalung interventional lung assist device (iLA). The iLA is a relatively low-resistance (5–6 mm Hg/[L/min]) oxygenator connected to cannulas in a femoral artery and vein. Thus, blood flow is driven by the arterial-venous pressure gradient.11 However, this promising device requires a mean arterial blood pressure of >70 mm Hg, and the patient’s circulation has to tolerate an arteriovenous shunt volume of 1.0–2.5 L/min to achieve adequate gas transfer. Thus, the iLA does not offer RV unloading or support. Furthermore, very little oxygen transfer is achieved. Therefore, the iLA is mostly used in patients with an intolerable CO2 retention but with acceptable oxygenation. Another major drawback of the iLA is that ambulatory use is impossible because of femoral cannulation.

Another possible solution may be a thoracic artificial lung consisting of a low-resistance oxygenator connected in parallel with the lung via the PA and the left atrium. This creates a low-resistance blood flow path with gas exchange that can unload the RV and reduce RV strain. Recent, highly positive results achieved by long-term large animal models12 lead to the introduction and initial experience of a paracorporeal artificial lung in humans with successful support periods over several weeks.13 The struggle with a centrally attached artificial lung is that it requires an invasive thoracotomy in severely ill patients, exposing this particular patient population to a considerable risk of anesthesia and major cardiac surgery. In addition, the formation of intrathoracic adhesions because of induced injuries results in a surgically difficult lung transplantation.

Another rather invasive method to support pulmonary and RV failure is venoarterial ECMO, which is occasionally used as a bridge to lung transplantation.7 However, for most adult patients with unresponsive severe respiratory failure, venovenous support is the method of choice. The venovenous configuration contains numerous advantages in comparison with the venoarterial configuration. Examples are the lower incidence of neurologic complications, the lack of arterial compromise, the potential for a single venous cannula for drainage and reinfusion, and the preservation of pulsatile perfusion. Today’s ECMO technology allows even the application in an extubated and alert patient. However, vv-ECMO does not provide circulatory support.

Early experimental studies in the mid-1960s and clinical observations in the mid-1980s have suggested that an interatrial shunt might be beneficial for the treatment of RV failure.14,15 Therefore, despite causing a slight hypoxemia, atrial septostomies are occasionally used to bridge patients to lung transplantation.6 In isolated severe hypertension, the drop in arterial oxygenation can be offset by an increase in CO provided by unloading the RV. However, if respiratory deficit is also present, the resultant hypoxia may be too severe. Previous acute and nonrecovery experiments conducted in our laboratory proved that a 1 cm diameter ASD permitted enough shunting to maintain normal CO while vv-ECMO maintained normal arterial blood gases over a period of 4 hours.

This study was designed to prove this concept in an alert large animal model. In summary, our results indicate that right-to-left atrial shunting in combination with vv-ECMO established with a double lumen cannula for drainage and reinfusion is capable of supporting RV function, maintaining normal CO, and maintaining near-normal gas exchange in a chronic, awake animal model. Cardiac output was maintained at a normal level for sheep of this weight, despite a significant reduction in PA flow over a period of 60 hours. One big advantage of this approach is that you do not need to be restrictive in ASD creation because oxygenized right atrial blood is supplied by vv-ECMO support.

Unfortunately, there was no reliable method applicable to determine the shunt fraction to show the significance of the ASD and its impact on maintaining CO. An echocardiography in awake and standing sheep is extremely unreliable according to our experiences because of the angle and shape of the sheep’s chest that is longitudinal oval compared with humans that are transversely oval with better echo access to the heart. Also, the possibility to use venous and arterial blood gases to calculate the shunt fraction is not sufficiently reliable because the shunt fraction in a standing sheep is depending on many factors, such as phase of inspiration, phase of cardiac cycle, and thoracic pressure. Last but not least, a vv-ECMO was in place with arterial return to the right atrium complicating the possibility to use blood gases. However, according to our previous studies using an extracardial interatrial shunt, the shunt fraction increases with banding of the PA.9,10 The patency of the ASD was verified during necropsy, showing a mean ASD diameter of 1 cm. Some reports describe the use of special stents to keep an interatrial communication open performing an ASD in patients experiencing arterial pulmonary hypertension.5 This is also recommended especially in adult patients because of a thick muscular septum. In our experiment, stenting the ASD would be closer to the clinical setting; however, we considered stenting for a 60 hour period as not necessary according to our previous studies.

Oxygen delivery under the aid of extracorporeal venovenous support fell significantly over the first 24 hours of the experiment. However, this drop in oxygen delivery was because of hemodilution during ECMO rather than a drop in CO. Blood transfusions in the first 24 hours of ECMO support would likely have eliminated this issue. Arterial PCO2 remained at normal levels over the course of the experiment. Ultimately, ECMO should be able to maintain sufficient gas transfer clinically.

However, there are also obstacles associated with ECMO therapy. According to the mainly pediatric-oriented extracorporeal life support organization (ELSO) registry, out of approximately 40,000 ECMO runs, an average of 2.7 complications occurred with an overall survival rate of 76%. The incidence of complications in this study confirms the experience of ELSO registry. Two of the seven animals experienced complications more or less associated with ECMO therapy during our experiment. There are hints that pumpless technologies such as the paracorporeal artificial lung attached in parallel with the lung from the PA to the left atrium might cause lesser blood damages and complications. However, these paracorporeal artificial lung experiments were performed without high RV afterload.

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Potential Limitations

The presented support mode was intended for patients experiencing chronic pulmonary hypertension caused predominantly from pathologies in the peripheral vascular tree and consecutive RV failure. Our model, however, is more similar to acute RV failure similar to a severe pulmonary embolism. However, this new approach is designed for critically ill patients, who have experienced an acute exacerbation of their disease state leading to a severe deterioration of pulmonary hypertension and RV failure. In addition, we believe the model used here is more challenging because the RV has not yet accommodated to the high afterload and is thus more prone to failure. Different results may be achieved using animals with chronic pulmonary hypertension and a partially compensated RV. Another limitation of this study is the induced respiratory distress caused by the thoracotomy. A closed-chest atrial septostomy would be preferable and better simulate the clinical application. Use of the thoracotomy likely included increase blood loss, inflammation, and postoperative weakness in these animals that detrimentally affected outcomes.

Lastly, there was no reliable means available to document the shunt fraction and volume unloading of the RV. Transthoracic echocardiography is extremely difficult to perform in sheep, and intracardiac echocardiography was not available. In addition, the use of venous and arterial blood gases to calculate the shunt fraction was not possible because of the return of inadequately mixed venous and oxygenated ECMO blood to the right atrium. However, our previous studies using an extracardial interatrial shunt indicate that the shunt fraction increases with banding of the PA.9,10 Accordingly, the ASD was patent at necropsy, with a mean diameter size of 1 cm.

The next phase of this work will be to perform longer term studies using closed-chest, catheter-based septostomies and intracardiac echocardiography for more detailed analysis of RV function. The first successful patient reports have demonstrated the effectiveness of this approach although without detailed description of the physiology.16

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Conclusions

The combination of an ASD with vv-ECMO is sufficient to unload the RV sufficiently to maintain normal CO and provide sufficient gas exchange in a long-term awake animal. This procedure has promise as a clinical bridge to lung transplant.

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References

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right ventricular failure; pulmonary failure; ECLS; lung transplant; septostomy

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